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Biomedical subjects

L J Dumble

Publications and source records attributed to L J Dumble.

52 records · Page 3Linked to original sources
PubMed1986

Characterisation of cyclosporine-induced suppressor cells in murine delayed-type hypersensitivity responses.

The effect of Cyclosporine A (CsA) on T cell-mediated delayed-type hypersensitivity (DTH) reactions to murine alloantigens was analysed by transferring spleen cells from sensitised and suppressed mice into irradiated naive recipients. Selective removal of Thy1+, Ly1+ or Ly2+ cells prior to intravenous transfer of cells from alloantigen-sensitised mice showed that Ly1+ Thy1+ cells transferred sensitivity. Concomitant treatment of mice with alloantigen and CsA suppressed the DTH response to alloantigens, and spleen cells transferred from these suppressed mice abrogated the response of sensitised cells transferred at the same time. The suppressor cells were strain-restricted and antigen-specific with the surface phenotype Thy1+, Ly1-Ly2+.

Animals↗
PubMed1986

Effects of cyclosporin A, antilymphocyte serum and donor-specific transfusions on murine delayed-type hypersensitivity and skin graft survival.

The effect of immunosuppressive reagents cyclosporin A (CsA) and rabbit anti-mouse antilymphocyte serum (ALS) on the response to alloantigens was studied in inbred mouse strains. Alloantigen was given either as a cell suspension which induced a delayed-type hypersensitivity reaction (DTH), or as a full-thickness skin graft. Dose-response studies showed that DTH reactions in CBA mice sensitised to BALB/c cells were reduced to background levels when recipient mice were treated with 100 mg/kg CsA on days 0, 4 and 6 after primary alloantigenic challenge. The response to a second challenge was significantly decreased by CsA treatment during primary or secondary exposure to alloantigen and CsA was as effective as ALS in abrogating both primary and secondary DTH reactions. Survival of full-thickness grafts of BALB/c skin on CBA mice was increased from 9 to 23 days by ALS treatment on days -1 and +2, with grafts given on day 0. Long-term treatment with CsA, from day -14 to +12, also prolonged graft survival from 9 to 18 days but donor-specific transfusions, with or without concomitant ALS or CsA treatment, decreased graft survival and often sensitised the recipients. This occurred with transfusions administered from -63 to -7 days and on the day of grafting. Thus, in H-2 mismatched mice, both CsA and ALS treatments produced a state of tolerance when administered during short-term exposure to alloantigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Inhibition of whole blood antibody dependent cellular cytotoxicity by heat aggregated human IgG.

Inhibition of the whole blood antibody dependent cellular cytotoxicity (ADCC) of a lymphoblastoid cell line by heat aggregated human IgG (HAI) is described. Optimal sensitising antibody and effector cell concentrations were established to permit the detection of 0.1 microgram/ml HAI. Conditions which avoid the ADCC inhibitory effects of normal human sera were defined. Twelve paired normal human sera were stored at -70 degrees C for prolonged (greater than 3 years) and shorter (less than 6 months) periods of time. Sensitised sheep red cells were used to determine complement depletion in serum dilutions heated at 40 degrees C, 45 degrees C, 50 degrees C. Concentrations of human IgG (1 000-0.1 microgram/ml) were prepared in foetal calf serum before heating at 63 degrees C for 30 min to aggregate the IgG. ADCC inhibitory activity, frequently characteristic of normal human serum was minimised (less than 10%) when sera were stored at -70 degrees C and heated to 50 degrees C for 30 min to inactivate serum complement. This assay provides an economical, reproducible and sensitive test for the detection of circulating IgG complexes.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Enhanced renal allograft survival from azathioprine/steroid modified antibody-dependent cellular cytotoxicity.

Serial antibody dependent cellular cytotoxicity (ADCC) effector cell function estimates and renal biopsies were obtained from 74 recipients to determine the ADCC modifications induced by azathioprine/steroid therapy and the histological character of rejection associated with the modifications. Recipients with suppressed ADCC did not experience rejection episodes while recipients with non-suppressed ADCC suffered graft failure following steroid-resistant rejection. The majority of recipients experienced reversible rejection episodes which were preceded by increased ADCC activity in the five day period preceding the commencement of high-dose steroid anti-rejection therapy. It was concluded that ADCC was active in the rejection process, and that in vitro ADCC measurement provided a means of monitoring the modifications induced by azathioprine/steroid therapy which promote a post-graft term free of rejection episodes.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1980

Human renal allograft rejection is predicted by serial determinations of antibody-dependent cellular cytotoxicity.

The early recognition and prompt treatment of rejection may minimise damage to renal allografts. Preliminary studies showed whole blood effector cell function in a constant antibody-dependent cellular cytotoxicity (ADCC) assay system to be suppressed in recipients with stable renal function. To investigate the possible role of ADCC in the rejection process, serial estimates were performed in 29 consecutive recipients of cadaveric kidneys. The generation of ADCC, as measured in vitro, preceded the biochemical confirmation of an impending rejection episode by 3 to 5 days for 31 of 33 episodes experienced by 23 recipients. Statistical analysis (X2) demonstrated a highly significant correlation between ADCC generation as measured in vitro and subsequent episodes of graft rejection. In contrast, six recipients who did not experience rejection episodes during the first 3 months postgrafting showed no evidence of ADCC activity. Thus, ADCC may be used to identify rejection earlier than has previously been possible.

Antibodies↗
PubMed1977

HLA and chronic active hepatitis (CAH).

A family study of 2 parents and 5 SD identical (HLA-A1, A3, B7, B8) siblings, one of whom has 'classic CAH' has been used to demonstrate that in this family the maternally ingerited HLA-B8 antigen is not solely serving to mark genetic predisposition to this disease. The patient's lymphocytes both responded to, and stimulated those of her 4 siblings in MLR indicating the possible involvement of an HLA-D antigen in CAH. This HLA-D antigen could have been of paternal orgin, or could have been a result of a recombination event involving an HLA-D antigen liked to the maternal HLA-A2, B12 haplotype. The lymphocytes of the four helthy siblings were mutually unresponsive in MLR.

Chronic Disease↗
PubMedDate not supplied

Intrasplenic liver parenchymal cells in conjunction with low-dose rapamycin and cyclosporine induce a unique and specific prolongation of rat cardiac and small bowel allograft survival.

These experiments investigated the immunosuppressive properties of liver tissue. Brown Norway (BN; RT1n) rat heart allografts survived in untreated control Wistar Furth (WFu; RTl(u)) rat recipients for 6.2 +/- 1.5 days, while allografts in animals that received rapamycin (RAPA) 0.0075 mg/kg/day and cyclosporine (CsA) 0.375 mg/kg/day delivered for 14 days by continuous intravenous infusion (civi) using osmotic pumps in conjunction with intrasplenic (i.s.) saline survived to 18.4 +/- 1.3 days. i.s. addition of 3 M-KCl extracted BN hepatic antigen or unpurified BN hepatocytes (liver parenchymal cells-5 x 10(7)/kg), which exhibited a 4.8% class II antigen expression, and which alone failed to prolong allograft survival (MST = 6.0 +/- 1.4 days), increased heart allograft survival to 25.3 +/- 2.3 and 27.2 +/- 1.9 days, respectively (p < 0.01). Hepatocyte purification using Dynabeads and Percoll reduced class II expression to 0.9% and increased allograft survival to 32.8 +/- 1.6 days (p < 0.01). In contrast, the effect of 5 x 10(8)/kg BN erythrocytes, exhibiting only 0.1% class II expression, was much less (23.8 +/- 1.9 days). Administration i.s. of BN splenocytes or nonparenchymal liver cells, demonstrated by flow cytometry to exhibit a 47.3 or 55.1% expression of class II antigen, respectively, failed to induce any significant increase in allograft survival (18.4 +/- 4.6 and 19.4 +/- 0.5 days, respectively). Survival of BN rat small bowel allografts was increased in Lewis (LEW; RTl1) rat recipients treated with RAPA, CsA, and unfractionated BN hepatocytes from 10.2 +/- 1.9 to 21.2 +/- 1.5 days. Pretreatment with i.s. BN hepatocytes, 14 days prior to harvesting, reduced WFu lymphocyte responses to allogeneic stimulation with BN or ACI spleen cells by 75 and 70%, respectively. Addition of 1 x 10(5) unpurified donor-specific BN or third-party Buffalo (BUF; RTl(b)) hepatocytes, but not supernatant, to the responder wells of MLCs resulted in a 61 and 40% suppression, respectively, of the WFu lymphocyte response induced by BN allogeneic stimulation. These findings suggest that while class I MHC expression has a significant role to play in exerting the immunosuppressive effects of hepatocytes, other influences more specific to liver may also prevail.

Animals↗
PubMedDate not supplied

15AU81, a prostacyclin analog, enhances donor-specific hepatocytes to prolong the survival of rat heart but not small bowel allografts.

Prostacyclin analogs have previously been shown to have not only cytoprotective but also independent immunosuppressive effects. The effect of one such analog, 15AU81, to enhance the immunosuppressive effects of liver was investigated. We have previously demonstrated that cyclosporine (CsA) in conjunction with rapamycin (RAPA) potentiates class I+, class II- donor-specific hepatocytes to prolong rat cardiac and small bowel allograft survival. Brown Norway (BN; RT1n) hepatocytes alone (5 x 10(7)/kg, administered intrasplenically) failed to prolong the survival of BN heart allografts in Wistar Furth (WFu; RT1u) recipients, beyond that of untreated controls (MST = 7.2 +/- 0.8 days). Survival of BN hearts was increased to 11.4 +/- 1.7 days in WFu recipients treated with BN hepatocytes and 50 microg/kg/day 15AU81 administered by continuous s.c. infusion for 14 days using osmotic pumps (p < 0.05). The further addition of RAPA 0.0075 mg/kg/day and CsA 0.375 mg/kg/day delivered for 14 days by continuous i.v. infusion (CIVI) using osmotic pumps (a combination that alone prolonged BN heart allografts in WFu hosts to 18.4 +/- 1.3 days and in conjunction with BN hepatocytes prolonged survival to 27.2 +/- 1.9 days) prolonged allograft survival to 35.2 +/- 5.2 days. In contrast, the survival of small bowel allografts was not enhanced by 15AU81 administration. Survival of BN small bowel transplants in LEW recipients treated with hepatocytes alone (MST = 11.6 +/- 1.5 days) or hepatocytes plus 15AU81 (MST = 10.0 +/- 1.0 days) was similar to controls (MST = 10.2 +/- 1.9 days). Treatment with hepatocytes and RAPA/CsA increased survival to 21.2 +/- 1.5 days. The further addition of 15AU81 failed to augment this (MST = 17.0 +/- 1.9 days). In vitro WFu lymphocyte proliferative responses from animals pretreated with BN hepatocytes, 15AU81, or both treatments, for 2 weeks prior to harvesting, exhibited a reduction of at least 50%, compared to untreated controls upon allostimulation with irradiated BN or ACI spleen cells. These findings demonstrate that 15AU81 interacts favorably with hepatocytes either alone or in conjunction with RAPA and CsA to enhance their immunosuppressive effects on rat heart allograft survival. The failure to enhance small bowel allograft survival may be explained by the inability at this low dosage of 15AU81 to influence the intense graft versus host reaction elicited by small bowel transplants.

Animals↗